Myocardial failure is a major source of morbidity and mortality. Nearly one out of every 56 Americans (approximately 1.8 percent of the population) suffer from some forms of myocardial failure. Patients in acute heart failure often are supported on systemic administration of medications to increase the force of the myocardial contraction. Such agents generally are referred to as inotropes, and often are given in intensive care units and operating rooms to increase cardiac output and organ perfusion.
Pharmacologic inotropic agents generally are classified by their mechanisms of action. Three examples of categories are sympathomimetics, phophodiesterase inhibitors, and calcium sensitizers. Other inotropes also are known and work by distinctly different mechanisms. Although each of these compounds may be used to increase the inotropic state of the heart, the amount administered is often limited in order to minimize undesirable systemic side effects. Frequently the infusion of additional agents is required to counteract side effects of systemically delivered inotropic drugs.
For example, dopamine dosing is limited by the increase in the rate and irritability of electrical excitation of the heart that accompanies a desired inotropic effect. Ventricular irritability may be so severe, however, that powerful anti-arrhythmic agents may be required to attempt to stabilize the myocardial cells and prevent these life threatening conditions. Administration of milrinone, a phosphodiesterase inhibitor that increases intracellular cyclicAMP (an intracellular signaling molecule that increases intropy), may result in dilation of the arterioles and causes systemic vasodilation and hypotension. As a result, a vasoconstricting agent may need to be co-administered.
Controlled release drug delivery from devices implanted about or injected into cardiac tissue has been variously described. See, e.g., U.S. Patent Application Publication No. 2008/0095824 A1 to Struijker-Boudier et al. Many of these delivery schemes involve injection into the myocardium or other significant violation of the myocardial tissue, which generally is undesirable but is particularly so in a heart with poor myocardial contractility.
Furthermore, some localized delivery strategies are ineffective for improving myocardial contraction, for example, because the delivery strategy only provides drug to a small localized fraction of the myocardial cells and the inotropic agents are not delivered to a large enough surface area of myocardial tissue, in an effective amount throughout the area. For example, an injection or other pinpoint delivery does not deliver the drug evenly to a large, but select, region of the myocardium.
Similarly, other local delivery schemes, such as infusion of a solution comprising an inotropic agent via a catheter into the pericardial space, also may fail to target delivery of the inotropic agent to the particular areas of the myocardium that would improve contractility and/or may fail to provide effective tissue levels of the drug at those required sites. More specifically, an inotropic agent introduced into the pericardial space in this way would be diluted in the pericardial fluid that bathes the outer surface of heart (the epicardium), thereby undesirably inhibiting the ability to target specific portions of myocardial tissue where the agent is needed (as pericardial fluid potentially carries the drugs to areas of the myocardium that would not be beneficial or may clear the drug away from the heart and into the lymphatic system) and decreasing drug delivery to the tissues that are targeted (as dilution of the inotropic agent in the pericardial fluid undesirably decreases the concentration of the drug at the epicardial surface which reduces, according to mass transport kinetics, the rate at which the drug can diffuse into the tissue).
In light of the foregoing limitations associated with current approaches to administration of inotropic agents and to the administration of drugs to the myocardium, there remains a need for new devices, systems, and methods for local delivery of inotropic agents to the myocardium. In particular, devices and methods are needed to achieve effective myocardial tissue levels of the inotropic agent while reducing the systemic levels of the inotropic agent, without violating the myocardial tissues. It would also be desirable to provide sustained release systems able to passively deliver effective amounts of inotropic agent to the myocardium over sustained periods, for example, for several days or weeks following cardiac surgery or for several months, for use with ambulatory patients and patients having chronic heart conditions.